NEUROTROPHIN-4 5, BRAIN-DERIVED NEUROTROPHIC FACTOR, AND NEUROTROPHIN-3 PROMOTE SURVIVAL OF CULTURED VESTIBULAR GANGLION NEURONS AND PROTECT THEM AGAINST NEUROTOXICITY OF OTOTOXINS/

The ability of neurotrophin-4/5 (NT-4/5), brain-derived neurotrophic f actor( BDNF), neurotrophin-3 (NT-3), and nerve growth factor (NGF) to promote survival of postnatal rat vestibular ganglion neurons (VGNs) w as examined in dissociated cell cultures. Of the four neurotrophins, N T-4/5 and BDNF were equally effective but more potent than NT-3 in pro moting the survival of VGNs. In contrast, NGF showed no detectable eff ects. As expected, TrkB-IgG (a fusion protein of extracellular domain of TrkB and Fc domain of human immunoglobulin G) specifically inhibite d the survival-promoting effects by NT-4/5 or BDNF and TrkC-IgG fusion protein completely blocked that of NT-3. Immunohistochemistry with Tr kB, TrkA, and p75 antisera revealed that VGNs made TrkB and p75 protei ns, but not TrkA protein. Ototoxic therapeutic drugs such as cisplatin and gentamicin often induce degeneration of hair cells and ganglion n eurons in both auditory and vestibular systems that leads to impairmen t of hearing and balance. When cisplatin and gentamicin were added to the dissociated VGN culture in which the hair cells were absent, addit ional cell death of VGNs was induced, suggesting that the two ototoxin s may have a direct neurotoxic effect on ganglion neurons in addition to their known toxicity on hair cells. However, if the cultures were c o-treated with neurotrophins, NT-4/5, BDNF, and NT-3, but not NGF, pre vented or reduced the neurotoxicity of the two ototoxins. Thus, the th ree neurotrophins are survival factors for VGNs and are implicated in the therapeutic prevention of VGN loss caused by injury and ototoxins. (C) 1995 John Wiley & Sons, Inc.